Powders intended for compression into tablets for the pharmaceutical and healthcare industries must possess two essential properties: fluidity and compressibility. Fluidity is required so that the material can be transported through the hopper of a tableting machine and so that adequate filling of the dies occurs in the tableting machine to produce tablets of a consistent weight. Although powder flow can be improved mechanically by the use of vibrators, the latter can cause powder segregation and stratification. Powder flow properties can also be increased by incorporating minute amounts of a glidant such as fumed silicium dioxide or by granulation. Compressibility is the property of forming a stable, intact compact mass when pressure is applied. Some materials are known to compact better than others, e.g. paracetamol is poorly compressible whereas lactose compresses well, however as a general rule granulation improves compressibility. The same concerns apply to detergent powders intended for making high-density detergent granules and for compression into detergent pressings.
In applications of granules other than tablets, compressibility is usually not a concern, however granulation yield, granule strength and homogeneity of particle size distribution remain the basic requirements of industries involved in such applications and uses.
Granulation is a process of particle size enlargement of powdered ingredients which is carried out to confer fluidity, and optionally compressibility, to powder systems. Ideally, granulation should be relatively dust free (reduced dustiness minimises losses, inhalation and explosion risks during further use of the granules, such as tabletting) and provide an as small percentage of both fine and coarse particles as possible, and granules should be robust enough to withstand handling without breaking down. Other desired properties of granulated products include improved flow and handling which facilitates controlled metering; increased bulk density; reduced pressure loss for fluid flow through a packed bed; controlled dissolution rates; and substantially maintained surface area of the original particles.
Granulation is a particle design technology which finds application in a wide range of industries including mineral processing, agricultural products, detergents, pharmaceuticals, foodstuffs, bed packings for blast furnaces, catalysts, fertilisers and chemicals. Improper granulation causes significant problems in down-stream industrial processes such as caking, segregation and poor tableting performance.
A wet method for the preparation of tablets for the pharmaceutical industry is the wet granulation process which involves a number of stages as follows. First, the drug substance is blended, if needed, with an inert diluent or filler (such as lactose or dicalcium phosphate) in a powder mixer in order to produce a uniform dispersion of the drug in the filler. Then in a second step the blended mixture is wetted by means of a liquid phase or solvent including, if needed, a binder (also known as adhesive or granulating agent or binding agent). The liquid phase or solvent must be volatile, so that it can be easily removed by drying, and non-toxic. It may be for instance water or a lower alcohol, such as isopropanol, ethanol or methanol, either alone or in combination. Because of their flammability and the consequent requirement for flame-proof equipment, organic solvents are used only for water-sensitive drugs or effervescent drug formulations or when a rapid drying time is required. Suitable binders include polyvinylpyrrolidone, acacia mucilage, gelatin, cellulose derivatives and starch mucilage. The binder is usually introduced at this stage as a solution or dispersion in the liquid phase, or the binder may also be mixed in the dry powder (the so-called “dry binder addition”). The wetting step is usually carried out in the same apparatus as the blending step. The damp mass obtained is then passed through a coarse sieve, usually of mesh size 1-2 mm, yielding particles, for instance by means of an oscillating granulator in which a rotor oscillating about its horizontal axis passes the damp material through the screen, or by means of a comminutor containing a number of rapidly revolving blades. After the granulation step, granules are now dried by means of a tray drier or a fluidised bed drier or by vacuum or microwave, resulting in a coarse free-flowing solid. The granule size at this point being usually considerably larger than required for tabletting (the usual average granule size for tabletting being in a range from about 250 to 700 μm), a sizing step including a comminution stage followed by sieving will usually be needed for breaking agglomerates of granules and removing the fine material which can be recycled. After the sizing step, granules are ready for blending, if needed, with additives such as lubricants, glidants, disintegrants, flavours, colorants and the like, before being transported to the compressing device where they are compressed in a die by the application of forces via two punches.
Extrusion is another way of producing a relatively dense granule, such as may be suitable for tabletting, from a low density material. An extruder typically comprises a barrel having a chamber; means for supplying material to be mixed and extruded to said chamber, a shaft in said chamber with material advancing means thereon such as an extrusion screw for advancing material toward one end of said chamber, and a die assembly mounted on the front end of said shaft and having extrusion die port means, such as one or more profiled or slot-shaped orifices, through which said material has to be forced to produce an extrudate of the required section, so that a specific pressure gradient is created within the die. For instance, U.S. Pat. No. 3,642,406 discloses a mixer-extruder combination of the latter type, further having means for revolving and reciprocating the shaft to mix and advance the material, wherein the die assembly has radially extending extrusion die port means and includes a rearwardly extending sleeve spaced radially from the shaft to define material issuing passage means leading to said port means. U.S. Pat. No. 5,240,400 discloses another embodiment of a screw-type extrusion granulating apparatus for extruding a moistened powder material into granules, said apparatus comprising a die in the shape of a dome and having a plurality of extrusion openings oriented radially with respect to the dome shape of said die and selected to be of a size corresponding to the desired diameter of the granules, i.e. even as small as about 0.3 to 0.6 mm. FIG. 2 of this patent clearly illustrates the maximum pressure reached in the area of the extrusion die. U.S. Pat. No. 4,890,996 also discloses a continuous granulator of the double-screw type for continuously melting, kneading and granulating macromolecular or resin materials, the said granulator including a mechanism by which the degree of kneading can be controlled and prevents lateral communication between the screw ends, the said granulating machine including a cutting unit having a screen and dies.
Although continuous processing would offer significant advantages (automation; reduction of batch to batch variation, labour cost and processing time) over batch production of pharmaceutical compositions, granulation techniques until now have been mainly confined to the use of mixer granulators and fluidised bed granulators. Although continuous granulating machines are widely used in the resin and polymer industry, very rare use has been made of continuous extrusion for granulating drug formulations prior to tabletting in the pharmaceutical or veterinary industry or for granulating food components or food additives. A short review of such few attempts is now provided herewith. Gamlen et al. in Drug Development and Industrial Pharmacy (1986) 12:1701-1713 disclosed production of paracetamol extrudates with a high drug loading (80% by weight) in the presence of 20-28% water by means of a Baker-Perkins MP50 mixer/extruder, explaining that the latter offers significant advantages by reducing the number of pieces of equipment required for extrudate manufacture. The extrudates thus obtained within a temperature range from 31 to 50° C. however had a high incidence of defects such as surface roughness and shark skinning (i.e. cracks penetrating deeply into the core of the extrudate). Furthermore, in the absence of a binder (hydroxypropylmethylcellulose), extrusion was associated with partial screen blockage at all moisture contents and marked irregularities in the rate of extrusion. Increasing the moisture content up to 28% resulted in an improvement in extrudate quality but also in more extensive clumping together of the extrudates to form aggregates. Summarising, Gamlen et al. faced the problems of equipment blocking at the lower water contents and of particle sticking at the higher water contents which still remain to be solved. In addition, the relatively high water contents used by Gamlen et al. necessarily induce a long post-processing drying step which is therefore significantly power-consuming and economically inefficient.
Similarly, Lindberg in Manufacturing Chemist (December 1988) 35-38 reported the continuous wet granulation of an effervescent mixture of 2 parts anhydrous citric acid and 1 part sodium bicarbonate by means of dehydrated ethanol as the granulating liquid in an extruder Baker Perkins MPF 50D comprising a feeding zone, a mixing zone and a discharge zone, wherein the powder inlet port is located above the feeding zone of the extruder and the granulating liquid inlet port is located above the mixing zone, wherein the paddles in the mixing zone provide intense shear mixing and wherein the discharge screws in the discharge zone help in developing the die pressure in the die plate which is attached at the extruder exit. While using residence time from 17 to 45 seconds, but without specifying ethanol concentration, Lindberg reported first the obtention of extrudates consisting of 5-10 mm long wet spaghetti, then after 30 minutes operation appearance suddenly changed to about 10 cm long spaghetti, indicating a blockage of the liquid injection nozzle. Summarising, Lindberg experienced the same technological problems as Gamlen et al. (cited supra), confirming significant shortcomings of the extrusion granulation technique in the drug formulation industry, and indicating the desirability for improvements in the granulating equipment for that purpose.
Leuenberger in European Journal of Pharmaceutics and Biopharmaceutics (2001) 52:289-296 reports on a quasi-continuous production line developed by Glatt A G (Pratteln, Switzerland) for avoiding scale-up problems in the pharmaceutical industry, the said production line being based on the principle of a semi-continuous production of mini-batches (sub-units) in a high-shear mixer/granulator which is connected to a continuous multicell-fluidised bed dryer. The article additionally reports on using this production line for granulating mixtures of lactose and maize starch with the aid of about 14.3% to 18.6% by weight of purified as the granulating liquid, again inducing a time- and power-consuming drying step. While admitting that this concept is not entirely continuous, the article insists on the fact that a technology transfer from processes with high production volumes has so far been less than successful in the case of continuous processing of pharmaceutical granules, and that in the pharmaceutical industry the batch-type wet granulation process cannot be so easily transformed into a continuous process.
Keleb et al. in International Journal of Pharmaceutics (2002) 239:69-80 disclosed a continuous twin screw extrusion process for the wet granulation of α-lactose monohydrate and investigated the influence of various parameters on the properties of granules and of tablets obtained by compressing the granules after wet sizing the extrudates, oven-drying and sieving. The process involved a co-rotating twin screw extruder having a feeding zone, a first mixing zone, a first transport zone, a second mixing zone, a second transport zone, and a die zone feeding to a die block mounted on the extruder barrel. While, like previously cited authors, indicating that precautions should be taken to avoid machine blocking, Keleb et al. reported a granulation yield of 60% and a tensile strength of 0.50 MPa for the resulting compacted tablets. Again these results show that there is still room for significant improvement before achieving an efficient and reproducible continuous process applicable to the pharmaceutical industry.
Similar observations can be derived from prior art in the detergent industry. For instance, U.S. Pat. No. 5,018,671 provides an apparatus for the continuous granulation of high-density detergent granules of a predetermined size from a detergent powder, comprising a granulation chamber, a feeding port located at the top of the granulation chamber, a first discharging port located at the bottom of the granulation chamber, a second discharging port located at the side wall of the granulation chamber, one or more horizontally rotating stirring blades attached to a rotational shaft positioned at the bottom of the granulation chamber for stirring and mixing the detergent powder, and one or more vertically rotating grinding blades located above the one or more stirring blades and attached to a rotational shaft positioned at the side wall of the granulation chamber for grinding and classifying coarse detergent particles. The same reference provides a process for operating the said apparatus, comprising the steps of continuously feeding a detergent powder into the granulation chamber, granulating the detergent powder by stirring and mixing the powder with the one or more horizontally rotating stirring blade, and continuously discharging the high-density detergent granules thus formed through the second discharging port. Operating the apparatus at a material temperature of 25° C. to 45° C. with an average retention time of 5 to 10 minutes achieved detergent granules with a bulk density of up to 0.7 g/cm3.
U.S. Pat. No. 5,382,377 discloses producing detergent pressings by a process comprising extruding a homogeneous premix containing a plasticizer or lubricant into strands through a perforated die under a pressure of 25 to 200 bar, forming compacted granules thereof, and pressing said compacted granules under a pressure of 1 to 300 bar. This process achieves high-performance detergents with densities up to 1.5 g/cm3.
Both International patent application published as WO 01/89679 and U.S. Pat. No. 6,499,984 disclose a single pass continuous processing system for producing pharmaceutical granulation, comprising:    (a) powder and liquid feeders to feed at least one pharmaceutically active ingredient and additives;    (b) a twin screw wet granulator-chopper device for granulating the active ingredient and additives received from the powder and liquid feeders into a wet granular product said twin screw wet granulator-chopper including a housing surrounding said device, said housing including a non-extruding opening at the outlet thereof;    (c) conveying, loading, and levelling means for conveying the wet granulation from the outlet of said twin screw wet granulator-chopper, loading the wet granulation on a dryer belt, and levelling the wet granulation to a desired height;    (d) a drying apparatus for receiving the wet granulation from the dryer belt and drying the wet granulation using dielectric energy;    (e) conveying means for transporting the dried granulation from the drying apparatus for size reduction;    (f) a mill for reducing the dried granulation to particles of a desired size; and    (g) control means for controlling process variables of at least one of the powder and liquid feeders, the twin screw wet granulator-chopper, the conveying, loading, and levelling means, the drying apparatus, the conveying means, and the mill to optimize production of pharmaceutical granulation.This continuous processing system appears as a combination of known equipment, since for instance twin-screw granulators are well known from U.S. Pat. Nos. 4,890,996 and 3,730,663, and choppers (i.e. devices for cutting into small pieces) are common in pharmaceutical granulation equipment, as disclosed by Aulton in Pharmaceutics, the Science of Dosage Form Design (1988) 623-625.
Thus, there is a strong consensus in the prior art that continuous granulation equipment is based either on high-shear mixers or fluid bed granulators or on extruding means including a die and/or developing a pressure at the extruder exit. At the same time, there is a strong need in the art for improving the long-term operating conditions of a wet granulation process, in particular for drug formulations and pharmaceutical compositions, by solving the recurrent problems of machine blocking reported by the various authors herein-above. It has been postulated that these problems may be due to the use of granulating equipment originally designed for resins and polymers whereas pharmaceutical compositions and foodstuffs, contrary to resins and polymers, are susceptible of physical and/or chemical interaction with the granulating liquid (usually water and/or a lower alcohol). There is also a need in the art for improving the granulation yield of a wet granulation process during long-term operations, i.e. for high production volumes. There is also a need in the art for the design of granulation equipment suitable for various powder materials, including chemicals, catalysts, detergents, drug formulations and foodstuffs, and which is simple and inexpensive in construction and maintenance. Furthermore, there is a need in the art for making drug formulations which have a reduced occurrence of certain defects such as shark skinning. Finally, there is a need in the art for making granules from pharmaceutical compositions or excipients which, when compacted into tablets, provide improved tablet properties, in particular higher tensile strength. Desirably, the continuous granulation process and equipment should be suitable for a very wide range of biologically-active substances, including those which are moisture-sensitive and/or heat-sensitive, i.e. should be able to operate at short residence times and low temperatures. Also desirably, it should be able to save energy and reduce the overall processing time by shortening the subsequent drying step duration. All the above cited needs constitute the various problems which the present invention intends to solve.